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In February we ran a story on the first 3D-printed human stem cells. The article described printing whole cells in droplet form, which then aggregate into small spheroids of tissue. The fact that several well-informed readers initially thought the cells themselves were being printing from scratch here, was not just our lack of clarity but an indication that the science to do so was not unthinkable. Now, a group of chemists from Oxford has developed a new technique to print synthetic cell microdroplets into complex 3D geometries.

These droplet cells have some interesting capabilities. During the print process they are vested with a lipid bilayer and can be tailored to express individual proteins. These proteins stabilize their interconnection and form pathways for electrical communication reminiscent of neural tissue. After printing, the nascent structures undergo secondary modification in which they respond like real biological tissue to gradients in temperature, pH and osmolarity to evolve structure where further stability is ensured.

Higher end 3D printers for tissue engineering have sufficient resolution to print on the scale of cells. A red blood cell (RBC), for example, has a narrowly prescribed functional role yet it still can have considerably variance in size across species. While human RBCs are typically 7um in diameter with a volume of 90 femtoliters, those belonging to the salamander Amphiuma might average 65um with a volume of 10,000 fL (10 picoliters). For the studies described here, the printing was done on the picoliter scale, with aqueous droplets up to 65 pL proving to be the most stable.

To assemble these structures, researchers at Oxford built two custom piezoelectric droplet generators. Drops were delivered through precision glass capillary tubes which could also suck back excess oil after they were deposited. The waveform of each mechanical cycle could be perfectly controlled, as could the speed at which drops were generated. Networks of up to 35,000 drops were assembled up to total size of around a millimeter. The printing could be done in pure oil, or alternatively within select pockets of oil maintained in a more biological scenario where the oil drops were suspended within a larger aqueous solution.

Printing tissues with what is effectively caviar has a unique set of challenges. A structure that appears stable under one set of conditions can quickly morph as parameters change. This sensitivity to the local environment, however, is exactly what is needed to evolve responsive, yet predictable form. The researchers could control the osmolarity of the the drops by manipulating their interior salt concentrations individually. When rows of one concentration were printed atop a row with a different concentration, the structure could be made to fold into complex geometries on timescales that allowed the whole print to finish before it began to flex.

Creating electrically-active components is also another way to add unique capabilities to these structures. To this end, the researchers also printed a subset of droplets containing a protein known as alpha-hemolysin (αHL), which is derived from staphylococcal bacteria. αHL seeks out its home in lipid membranes and is able to form junctions which link two sets of membranes together along with a central pore. Using these junctions, droplets could be configured into conductive pathways through which ions could flow. By hooking up special droplet control nodes of the network to silver electrodes, different conductive pathways could be created.

Inside real cells, lipid structures are tweaked through the cooperation of thousands of different kinds of proteins, each expressed in thousands of copies. Much of the intrinsic behaviors of these lipid components are inherent in the complex hydrophobic interactions of water and fat molecules. For example, altering ion concentrations and adding membrane proteins to a set of 40 nanometer lipid vessicles, might bias them instead into organizing into a fewer number of 60nm spheroids. Additionally, tricks like transitioning a row of spheroids into tubes, and tubes into disks, is the bread and butter cellular housekeeping.

In the paper and extensive supplementary information, the authors did an in-depth thermodynamic analysis of some of these behaviors in their droplet networks. They also hinted at the possibility of this type of research eventually being used to develop 3D neural-like circuitry for information processing. 3D-printed brains would be something to behold, however in the jelly-world, post-print dynamics reign supreme. Harnessing those effects to better mimic real cells will be the next challenge.

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